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ABSTRACT Background In healthy individuals, exercise and amino acid availability act synergistically to stimulate muscle anabolism. However, this interaction may be impaired in individuals with obesity. Objective We examined whether acute aerobic exercise alters amino acid-stimulated muscle protein synthesis during immediate postexercise recovery in adults with obesity. Methods Sixteen sedentary adults with a body mass index >30 kg/m 2 underwent a stable-isotope tracer infusion to measure mixed-muscle protein fractional synthesis rate (FSR) in the basal/fasted state and during an amino acid infusion, either with or without prior aerobic exercise. Participants were randomly assigned to receive either amino acid infusion alone (AA) or 45 min of cycling exercise at ∼65% heart rate reserve immediately before amino acid infusion (EX + AA). Results Amino acid infusion increased muscle protein FSR in the AA group ( P < 0.0001) but not in the EX + AA group ( P > 0.05), and the amino acid-stimulated increase in FSR was 78% lower in EX + AA than in AA ( P < 0.01). The amino acid infusion increased ( P < 0.05) plasma amino acid concentrations in both groups. However, during the amino acid infusion, plasma concentrations of essential and branched-chain amino acids, including leucine, were lower in EX + AA than in AA ( P < 0.05). Moreover, across participants, absolute changes in muscle protein FSR were positively associated with plasma leucine concentrations during the amino acid infusion ( P < 0.05). Conclusions These findings show that, in individuals with obesity, acute aerobic exercise markedly attenuates amino acid-stimulated muscle protein synthesis during early postexercise recovery. These findings have important implications for designing nutritional strategies to optimize muscle anabolism in this population.

Obesity is associated with altered skeletal muscle protein metabolism. While plasma amino acids (AA) stimulate protein synthesis in muscle, it remains unclear how aerobic exercise modifies this response in obesity. In this study, we evaluated basal and amino acid-stimulated skeletal muscle protein fractional synthesis rate (FSR) in humans with obesity, induced by a primed, constant AA infusion (15% Clinisol; 4 mg·kg FFM-1·min-1), immediately after a single bout of acute aerobic exercise. We studied two groups of subjects with obesity: Group 1: AA infusion alone for 240 mins (AA; N = 8; BMI: 34.9 ± 1 kg/m 2 ; body fat percent: 35.2 ± 2) and group 2: acute aerobic exercise followed by AA infusion for 240 mins (AA+EX; N=8; BMI: 36.1 ± 2 kg/m 2 ; body fat percent: 42.4 ± 2). Subjects in the AA+EX group performed 45 minutes of cycling on a stationary bike at 65% VO2 max, and their amino acid infusion started immediately after the exercise ended. A d10-leucine tracer was infused for the entire duration of the study to measure mixed-muscle protein FSR (MMP-FSR). Muscle biopsies from the vastus lateralis were taken at baseline, 45 mins after the start of the amino acid infusion and at the end of the infusion study to determine MMP-FSR. Baseline MMP-FSR values did not differ between groups (p > 0.05). Participants receiving the AA infusion alone exhibited a significant increase in MMP-FSR from baseline to post-infusion (0.060 ± 0.005 to 0.119 ± 0.011 %/hr; p < 0.0001), whereas the AA+EX group showed no significant change from baseline (0.067 ± 0.004 to 0.084 ± 0.009 %/hr; p > 0.05). Plasma insulin concentrations increased significantly in response to the amino acid infusion (p < 0.0001) but did not differ between groups (p > 0.05). Baseline amino acid concentrations were not different between groups (p > 0.05). Among the plasma amino acids (μmol/L) changed, baseline plasma leucine (AA:137 ± 8, AA+EX: 144 ± 10; p > 0.05) increased significantly in both groups during AA infusion but was higher in the AA (424 ± 15) than the AA+EX (226 ± 13) group (p< 0.0001). Similarly, baseline plasma valine (AA: 226 ± 7, AA+EX: 234 ± 19; p > 0.05) increased significantly in both groups during AA infusion but was higher in the AA (553 ± 28) than the AA+EX (456 ± 23) group (p< 0.002). In contrast baseline arginine (AA: 59 ± 5, AA+EX: 71±11; p > 0.05), although it increased significantly in both groups during AA infusion, was lower in the AA (197 ± 3) than the AA+EX (266 ± 11) group (p< 0.0001). Despite marked increases in plasma amino acid and insulin concentrations, the AA+EX group exhibited a blunted muscle protein synthesis response to amino acid stimulation compared with the AA group. In conclusion, aerobic exercise blunts the amino acid-stimulated increase in muscle anabolism in the immediate period after exercise in humans with obesity. This research was supported by the National Institutes of Health/ National Institute of Diabetes and Digestive and Kidney Diseases. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.

Introduction Asthma is a multifactorial disease influenced by genetic and environmental factors, including diet. The gut microbiome contributes to airway inflammation via the gut-lung axis, partly through production of short chain fatty acids (SCFAs) from bacterial fermentation of dietary fiber. We hypothesized that dietary fiber supplementation could modulate the gut microbiome and increase SCFAs in children with asthma. Methods This is a double-blind, placebo-controlled trial of children who were randomized to consume 12 g of soluble corn fiber (SCF) as a supplement to their usual daily diet (50% the recommended daily fiber intake) or placebo for 4–6 weeks ( clinicaltrials.gov NCT03673618). Dietary surveys, asthma symptom questionnaires, fecal, blood and nasal samples were collected before and after the intervention period to quantify fiber intake, asthma control, nasal and gut microbiome, and serum short chain fatty acids (SCFAs). Results Of the 20 children enrolled, 15 completed the intervention with an average adherence rate of 83%. SCFA concentrations and gut microbiome changes varied by individual and treatment group. No significant differences in gut or nasal alpha or beta diversity were observed between groups post-intervention. However, differential abundance analysis showed a trend toward increased Bifidobacterium in the SCF group compared to placebo (ANCOM-BC p = 0.0004, FDR q = 0.073). Discussion Supplementation of 50% of recommended daily fiber intake had minimal impact on asthma symptoms, the microbiome, or SCFA levels. Future studies should consider higher fiber doses, different fiber types, or targeting individuals with low baseline fiber intake to account for observed variability in microbiome and SCFA responses. Clinical Trial Registration https://clinicaltrials.gov/study/NCT03673618 , identifier NCT03673618.

Abstract Rheumatoid arthritis (RA) causes immunological and metabolic imbalances in tissue, exacerbating inflammation in affected joints. Changes in immunological and metabolic tissue homeostasis at different stages of RA are not well understood. Herein, the changes in the immunological and metabolic profiles in different stages in collagen induced arthritis (CIA), namely, early, intermediate, and late stage is examined. Moreover, the efficacy of the inverse‐vaccine, paKG(PFK15+bc2) microparticle, to restore tissue homeostasis at different stages is also investigated. Immunological analyses of inverse‐vaccine‐treated group revealed a significant decrease in the activation of pro‐inflammatory immune cells and remarkable increase in regulatory T‐cell populations in the intermediate and late stages compared to no treatment. Also, glycolysis in the spleen is normalized in the late stages of CIA in inverse‐vaccine‐treated mice, which is similar to no‐disease tissues. Metabolomics analyses revealed that metabolites UDP‐glucuronic acid and L‐Glutathione oxidized are significantly altered between treatment groups, and thus might provide new druggable targets for RA treatment. Flux metabolic modeling identified amino acid and carnitine pathways as the central pathways affected in arthritic tissue with CIA progression. Overall, this study shows that the inverse‐vaccines initiate early re‐establishment of homeostasis, which persists through the disease span.

Neurodevelopmental disorders are associated with metabolic pathway imbalances; however, most metabolic measurements are made peripherally, leaving central metabolic disturbances under-investigated. Cerebrospinal fluid obtained intraoperatively from children with autism spectrum disorder (ASD, n = 34), developmental delays (DD, n = 20), and those without known DD/ASD (n = 34) was analyzed using large-scale targeted mass spectrometry. Eighteen also had epilepsy (EPI). Metabolites significantly related to ASD, DD and EPI were identified by linear models and entered into metabolite–metabolite network pathway analysis. Common disrupted pathways were analyzed for each group of interest. Central metabolites most involved in metabolic pathways were L-cysteine, adenine, and dodecanoic acid for ASD; nicotinamide adenine dinucleotide phosphate, L-aspartic acid, and glycine for EPI; and adenosine triphosphate, L-glutamine, ornithine, L-arginine, L-lysine, citrulline, and L-homoserine for DD. Amino acid and energy metabolism pathways were most disrupted in all disorders, but the source of the disruption was different for each disorder. Disruption in vitamin and one-carbon metabolism was associated with DD and EPI, lipid pathway disruption was associated with EPI and redox metabolism disruption was related to ASD. Two microbiome metabolites were also detected in the CSF: shikimic and cis-cis-muconic acid. Overall, this study provides increased insight into unique metabolic disruptions in distinct but overlapping neurodevelopmental disorders.

Coccidioidomycosis, or Valley Fever (VF), is a potentially lethal fungal infection that results in more than 200 deaths/year in the United States. Differential diagnosis and timely treatment of VF is made difficult due to presentation of vague symptoms that often mimic other pulmonary conditions. Accurate diagnosis therefore relies on a combination of clinical presentation, serology, radiography, histology and culture. These diagnostic methods are either costly, time‐consuming, invasive, or indeterminate. Previous studies have used MS‐based methods for the accurate diagnosis of similar fungal diseases as well as characterization of host‐fungal interactions. Herein, we present the first targeted plasma and urine liquid chromatography tandem mass spectrometry (LC‐MS/MS) profiling approach for the relatively non‐invasive, rapid and accurate detection of VF. In this targeted approach, 207 plasma metabolites and 231 urine metabolites were reliably detected using LC‐MS/MS. These metabolites, which are representative of more than 35 metabolic pathways of potential biological relevance, were monitored in 59 plasma samples and 88 urine samples acquired from excess clinical specimens taken from two groups of patients (48 VF patients and 99 non‐VF controls) at Mayo Clinic Arizona. Univariate and multivariate statistical analyses were performed to develop predictive plasma and urine biomarker panels. Pathway and enrichment analyses were performed to elucidate potential pathogenic mechanisms and therapeutic targets. Results of our univariate significance testing and multivariate model estimation informed the construction of a 3‐metabolite panel of plasma biomarkers ( q < 0.05 and VIP > 2; Fig 1) and a 9‐metabolite panel of urinary biomarkers ( q < 0.05 and VIP > 1; Fig 2). Receiver operating characteristic (ROC) curves (Fig 3) generated based on enhanced orthogonal partial least squares‐discriminant analysis (OPLS‐DA) models (Fig 4) showed excellent overall classification performance (99.5%), with 94.4% sensitivity and 97.6% specificity for plasma metabolites. Although urine metabolites were less accurate (92.5%), demonstrating 89.7% sensitivity and 88.1% specificity, they represent a substantial increase in diagnostic accuracy over currently available urinary antigen tests, which only report sensitivity of around 70%. Pathway analysis (Fig 5) and enrichment analysis (Fig 6) ubiquitously showed alterations in metabolic pathways related to fungal virulence, DNA/RNA synthesis and energy utilization, and host immune escape mechanisms. These results potentially reveal pathways or markers that could be targeted therapeutically. This study is the first‐ever MS‐based metabolomics approach for rapid and highly accurate diagnosis of VF. Support or Funding Information Support from the College of Health Solutions at Arizona State University, Arizona Biomedical Research Council (ABRC) grant# 16–162513 and American Achievement Rewards for College Scientists (ARCS) Foundation Award is gratefully acknowledged. This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .

Mutations in the γ2-subunit of AMPK (encoded by PRKAG2 gene) cause glycogen storage cardiomyopathy. We generated a mouse model with cardiac specific deletion of γ2-AMPK (cKO) to define its function in the heart. The cKO mice were born normal and remained indistinguishable from control mice under baseline conditions but developed greater cardiac hypertrophy and dysfunction after transverse aortic constriction (TAC). The total AMPK activity was normal in cKO hearts and it increased after TAC to the same extent as that of the controls. However, the γ2-AMPK activity was abolished in the cKO and the overall AMPK activity was maintained by a compensatory increase in the γ1-AMPK activity. The lack of γ2-AMPK selectively reduced hexokinase II in the cytosol resulting in decreases in glycogen content and NADPH levels. Knock-down of γ2-AMPK subunit in neonatal rat ventricle cardiomyocytes resulted in increased oxidative stress and exacerbated response to phenylephrine and H 2 O 2 , both were rescued by HKII overexpression. Taken together, these data identify isoform-specific functions of γ2-AMPK in regulating glucose and glycogen metabolism that are critical for cardiac response to stress. The results also indicate that the specific activation of γ2-AMPK is responsible for the glycogen storage cardiomyopathy associated with PRKAG2 mutations.

Abstract Breast cancer (BC) is a common cause of morbidity and mortality, particularly in women. Moreover, the discovery of diagnostic biomarkers for early BC remains a challenging task. Previously, we [Jasbiet al.J. Chromatogr. B.2019, 1105, 26−37] demonstrated a targeted metabolic profiling approach capable of identifying metabolite marker candidates that could enable highly sensitive and specific detection of BC. However, the coverage of this targeted method was limited and exhibited suboptimal classification of early BC (EBC). To expand the metabolome coverage and articulate a better panel of metabolites or mass spectral features for classification of EBC, we evaluated untargeted liquid chromatography quadrupole time-of-flight mass spectrometry (LC-QTOF-MS) data, both individually as well as in conjunction with previously published targeted LC-triple quadruple (QQQ)-MS data. Variable importance in projection scores were used to refine the biomarker panel, whereas orthogonal partial least squares-discriminant analysis was used to operationalize the enhanced biomarker panel for early diagnosis. In this approach, 33 altered metabolites/features were detected by LC-QTOF-MS from 124 BC patients and 86 healthy controls. For EBC diagnosis, significance testing and analysis of the area under receiver operating characteristic (AUROC) curve identified six metabolites/features [ethyl (R)-3-hydroxyhexanoate; caprylic acid; hypoxanthine; and m/z 358.0018, 354.0053, and 356.0037] with p &lt; 0.05 and AUROC &gt; 0.7. These metabolites informed the construction of EBC diagnostic models; evaluation of model performance for the prediction of EBC showed an AUROC = 0.938 (95% CI: 0.895–0.975), with sensitivity = 0.90 when specificity = 0.90. Using the combined untargeted and targeted data set, eight metabolic pathways of potential biological relevance were indicated to be significantly altered as a result of EBC. Metabolic pathway analysis showed fatty acid and aminoacyl-tRNA biosynthesis as well as inositol phosphate metabolism to be most impacted in response to the disease. The combination of untargeted and targeted metabolomics platforms has provided a highly predictive and accurate method for BC and EBC diagnosis from plasma samples. Furthermore, such a complementary approach yielded critical information regarding potential pathogenic mechanisms underlying EBC that, although critical to improved prognosis and enhanced survival, are understudied in the current literature. All mass spectrometry data and deidentified subject metadata analyzed in this study have been deposited to Mendeley Data and are publicly available (DOI: 10.17632/kcjg8ybk45.1).

Metabolites control immune cell functions, and delivery of these metabolites in a sustained manner modulate the function of the immune cells.